SpringerLink
Log in

The immunohistochemical expression of von Willebrand factor, T-cadherin, and Caveolin-1 is increased in kidney allograft biopsies with antibody-mediated injury

  • Original article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background

There are only a few reports evaluating the applicability of endothelial-damage markers analysis by immunohistochemistry (IHC) in kidney allograft samples. This study analyzed the expression of Caveolin-1 (Cav), von Willebrand factor (Vwf), and T-cadherin (Cad) in kidney biopsies and their association with antibody-mediated injury.

Methods

In this retrospective study, 114 cases with antibody-mediated changes (Banff, 2020) and 72 with interstitial fibrosis/tubular atrophy were selected. IHC for Cav, Vwf and Cad was performed and evaluated according to their qualitative expression in peritubular capillaries. The cases were grouped according to the presence of microvascular inflammation (MVI), donor-specific antibodies (DSA), C4d positivity and antibody-mediated rejection (AMR). A level of significance < 0.05 was adopted.

Results

Vwf expression was associated with MVI (p < 0.001), DSA (p = 0.016), C4d (p < 0.001) and AMR (p < 0.001), and was higher in DSA+/C4d+ cases despite MVI (p < 0.001). The expression of Cad correlated with MVI (p = 0.015), C4d (p = 0.005) and AMR (p = < 0.001). Cad was more expressed in chronic AMR compared with acute/active cases (p = 0.001). Cav expression was associated with MVI (p = 0.029) and AMR (p = 0.016) and was also higher in chronic AMR (p = 0.049). A combined score of Vwf and Cad was higher in AMR when compared with C4d without rejection and IF/TA cases (p < 0.001).

Conclusion

Vwf, Cad and Cav expression shows association with antibody-mediated injury and may be helpful to support AMR diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Puttarajappa C, Shapiro R, Tan HP. Antibody-mediated rejection in kidney transplantation: a review. J Transplant. 2012;2012:193724. https://doi.org/10.1155/2012/193724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Haas M. Evolving criteria for the diagnosis of antibody-mediated rejection in renal allografts. Curr Opin Nephrol Hypertens. 2018;27(3):137–43. https://doi.org/10.1097/mnh.0000000000000398.

    Article  PubMed  Google Scholar 

  3. Bhowmik DM, Dinda AK, Mahanta P, Agarwal SK. The evolution of the Banff classification schema for diagnosing renal allograft rejection and its implications for clinicians. Indian J Nephrol. 2010;20(1):2–8. https://doi.org/10.4103/0971-4065.62086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Racusen LC, Halloran PF, Solez K. Banff 2003 meeting report: new diagnostic insights and standards. Am J Transplant. 2004;4(10):1562–6. https://doi.org/10.1111/j.1600-6143.2004.00585.x.

    Article  PubMed  Google Scholar 

  5. Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014;14(2):272–83. https://doi.org/10.1111/ajt.12590.

    Article  CAS  PubMed  Google Scholar 

  6. Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018;18(2):293–307. https://doi.org/10.1111/ajt.14625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant. 2009;9(10):2312–23. https://doi.org/10.1111/j.1600-6143.2009.02761.x.

    Article  CAS  PubMed  Google Scholar 

  8. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010;15(1):42–8. https://doi.org/10.1097/MOT.0b013e3283352a50.

    Article  PubMed  Google Scholar 

  9. Sis B, Jhangri GS, Riopel J, Chang J, de Freitas DG, Hidalgo L, et al. A new diagnostic algorithm for antibody-mediated microcirculation inflammation in kidney transplants. Am J Transplant. 2012;12(5):1168–79. https://doi.org/10.1111/j.1600-6143.2011.03931.x.

    Article  CAS  PubMed  Google Scholar 

  10. Sis B. Endothelial molecules decipher the mechanisms and functional pathways in antibody-mediated rejection. Hum Immunol. 2012;73(12):1218–25. https://doi.org/10.1016/j.humimm.2012.07.332.

    Article  CAS  PubMed  Google Scholar 

  11. Gragnano F, Sperlongano S, Golia E, Natale F, Bianchi R, Crisci M, et al. The role of von Willebrand factor in vascular inflammation: from pathogenesis to targeted therapy. Mediat Inflamm. 2017;2017:5620314. https://doi.org/10.1155/2017/5620314.

    Article  CAS  Google Scholar 

  12. Philippova M, Joshi MB, Kyriakakis E, Pfaff D, Erne P, Resink TJ. A guide and guard: the many faces of T-cadherin. Cell Signal. 2009;21(7):1035–44. https://doi.org/10.1016/j.cellsig.2009.01.035.

    Article  CAS  PubMed  Google Scholar 

  13. Nakada Y, Yamamoto I, Horita S, Kobayashi A, Mafune A, Katsumata H, et al. The prognostic values of caveolin-1 immunoreactivity in peritubular capillaries in patients with kidney transplantation. Clin Transplant. 2016;30(11):1417–24. https://doi.org/10.1111/ctr.12833.

    Article  CAS  PubMed  Google Scholar 

  14. Loupy A, Lefaucheur C, Vernerey D, Chang J, Hidalgo LG, Beuscart T, et al. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection. J Am Soc Nephrol. 2014;25(10):2267–77. https://doi.org/10.1681/ASN.2013111149.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, et al. The Banff 2015 Kidney Meeting Report: current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant. 2017;17(1):28–41. https://doi.org/10.1111/ajt.14107.

    Article  CAS  PubMed  Google Scholar 

  16. Ozdemir BH, Sar A, Haberal M. The importance of glomerular deposits of von Willebrand factor in human renal allografts. Ren Fail. 2006;28(4):315–21. https://doi.org/10.1080/08860220600577759.

    Article  CAS  PubMed  Google Scholar 

  17. Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al. The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020;20(9):2318–31. https://doi.org/10.1111/ajt.15898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Süsal C, Roelen DL, Fischer G, Campos EF, Gerbase-DeLima M, Hönger G, et al. Algorithms for the determination of unacceptable HLA antigen mismatches in kidney transplant recipients. Tissue Antigens. 2013;82(2):83–92. https://doi.org/10.1111/tan.12137.

    Article  PubMed  Google Scholar 

  19. Roufosse C, Simmonds N, Clahsen-van Groningen M, Haas M, Henriksen KJ, Horsfield C, et al. A 2018 reference guide to the Banff classification of renal allograft pathology. Transplantation. 2018;102(11):1795–814. https://doi.org/10.1097/TP.0000000000002366.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sapir-Pichhadze R, Curran SP, John R, Tricco AC, Uleryk E, Laupacis A, et al. A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney Int. 2015;87(1):182–94. https://doi.org/10.1038/ki.2014.166.

    Article  CAS  PubMed  Google Scholar 

  21. Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012;81(7):628–39. https://doi.org/10.1038/ki.2011.497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. De Serres SA, Noël R, Côté I, Lapointe I, Wagner E, Riopel J, et al. 2013 Banff criteria for chronic active antibody-mediated rejection: assessment in a real-life setting. Am J Transplant. 2016;16(5):1516–25. https://doi.org/10.1111/ajt.13624.

    Article  PubMed  Google Scholar 

  23. Hayde N, Bao Y, Pullman J, Ye B, Calder RB, Chung M, et al. The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol. 2013;8(12):2141–8. https://doi.org/10.2215/cjn.04240413.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hayde N, Broin P, Bao Y, de Boccardo G, Lubetzky M, Ajaimy M, et al. Increased intragraft rejection-associated gene transcripts in patients with donor-specific antibodies and normal biopsies. Kidney Int. 2014;86(3):600–9. https://doi.org/10.1038/ki.2014.75.

    Article  CAS  PubMed  Google Scholar 

  25. Dominy KM, Willicombe M, Al Johani T, Beckwith H, Goodall D, Brookes P, et al. Molecular assessment of C4d-positive renal transplant biopsies without evidence of rejection. Kidney Int Rep. 2019;4(1):148–58. https://doi.org/10.1016/j.ekir.2018.09.005.

    Article  PubMed  Google Scholar 

  26. Gupta A, Broin P, Bao Y, Pullman J, Kamal L, Ajaimy M, et al. Clinical and molecular significance of microvascular inflammation in transplant kidney biopsies. Kidney Int. 2016;89(1):217–25. https://doi.org/10.1038/ki.2015.276.

    Article  CAS  PubMed  Google Scholar 

  27. Halloran PF, Merino Lopez M, Barreto PA. Identifying subphenotypes of antibody-mediated rejection in kidney transplants. Am J Transplant. 2016;16(3):908–20. https://doi.org/10.1111/ajt.13551.

    Article  CAS  PubMed  Google Scholar 

  28. Aubert O, Loupy A, Hidalgo L, Duong van Huyen JP, Higgins S, Viglietti D, et al. Antibody-mediated rejection due to preexisting versus. J Am Soc Nephrol. 2017;28(6):1912–23. https://doi.org/10.1681/asn.2016070797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ivanov D, Philippova M, Antropova J, Gubaeva F, Il**skaya O, Tararak E, et al. Expression of cell adhesion molecule T-cadherin in the human vasculature. Histochem Cell Biol. 2001;115(3):231–42. https://doi.org/10.1007/s004180100252.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the patients and the staff of the Transplantation Division of the General Hospital of Fortaleza.

Author information

Authors and Affiliations

  1. Medical Sciences Postgraduation Program, Department of Clinical Medicine, Faculty of Medicine of the Federal University of Ceará, Monsenhor Furtado St, s/n, Fortaleza, CE, 60430-275, Brazil

    André Costa Teixeira, Fábio Távora & Tainá Veras de Sandes-Freitas

  2. ARGOS Patologia, 5753 Santos Dumont av, Room 1604, Office Tower, Fortaleza, Ceará, 60175047, Brazil

    André Costa Teixeira & Fábio Távora

  3. Faculty of Medicine of State University of Ceará, 1700 Silas Munguba St, Itaperi, Fortaleza, CE, 60441-750, Brazil

    Melissa Lou Fagundes de Deus e Silva & Renan Martins Gomes Prado

  4. Division of Transplantation, General Hospital of Fortaleza, 900 Ávila Goulart St, Papicu, Fortaleza, CE, 60165-160, Brazil

    Ronaldo de Matos Esmeraldo & Tainá Veras de Sandes-Freitas

Authors
  1. André Costa Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fábio Távora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melissa Lou Fagundes de Deus e Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renan Martins Gomes Prado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ronaldo de Matos Esmeraldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tainá Veras de Sandes-Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André Costa Teixeira.

Ethics declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures were in accordance with the ethical standards of National Health Council Resolution 466/12 and the Declaration of Helsinki. The study was approved by the Institutional Review Board (number 2.335.513).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Teixeira, A.C., Távora, F., de Deus e Silva, M.L.F. et al. The immunohistochemical expression of von Willebrand factor, T-cadherin, and Caveolin-1 is increased in kidney allograft biopsies with antibody-mediated injury. Clin Exp Nephrol 25, 305–314 (2021). https://doi.org/10.1007/s10157-020-01994-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-020-01994-6

Keywords

Search

Navigation